DESCRIPTION (Taken from the applicant's Abstract) Non-insulin dependent diabetes mellitus affects nearly 10 million Americans and costs the United States more than $20 billion a year. The specific molecular lesions responsible for the insulin resistance characteristic of this disease remain unknown. Recently, great progress has been made in identifying the initial signaling events in insulin action; however, the role of these molecules in the metabolic effects of insulin remains to be determined. The liver plays a central role in the regulation of carbohydrate and lipid metabolism, and hepatic insulin resistance is critical to the development of two of the clinical hallmarks of diabetes -- fasting hyperglycemia and hypertriglyceridemia. The goal of this study is to examine the role of the two best-characterized components of the insulin signal transduction system (phosphatidylinositol 3- kinase and the ras/MAP kinase pathway) in the regulation of hepatic carbohydrate and lipid metabolism. We will develop several methods to alter these signaling pathways (i.e., adenoviral vector infection, generation of inducible promoter stable transfectants) and examine the effects these specific perturbations on defined targets of hepatic insulin action in both isolated cell systems and in vivo using mouse models. Dr. Gabbay has a long-standing interest in the pathogenesis of diabetes, hepatic insulin action, and insulin resistance. This project will be conducted in the Endocrine Division of Beth Israel Hospital, Boston under the supervision of Dr. Jeffrey Flier. A major focus within the Division is the molecular dissection of the mechanisms underlying insulin resistance. The research environment provides state-of-the-art molecular biological and animal research facilities.